In drug development, clinical pharmacology studies are crucial to gather information to mitigate risks for the end user. Several studies are needed to determine how to safely administer the product to diverse patient populations. This data ultimately supports the recommendations found in the product label/SmPC. Examples of factors that need to be described include the impact of renal and hepatic impairment, age, drug-drug interactions, and food on the effect and safety of a drug.

Here, I delve into the fundamentals of clinical pharmacology studies, emphasizing their importance, and provide insights on conducting them effectively to optimize drug development outcomes.

What is clinical pharmacology?

Clinical pharmacology is the study of the interactions between drugs and the human body. Under this umbrella, pharmacokinetics (PK) can be described as how the body handles the drug (absorption, distribution, metabolism, excretion) and pharmacodynamics (PD) describes how the drug affects the body. The relationship between pharmacokinetics and pharmacodynamics of a drug is influenced by its physicochemical properties, the product/formulation, the administration route, and the physiology and behavior of the patient. All these factors need to be studied and described.

Clinical pharmacology is an interdisciplinary field that aims to extrapolate or generalize clinical data from a restricted Phase III population to the broader population. It also seeks to identify populations at risk for under- or overdosing. To do this, you need to study and evaluate drug-drug interactions, pharmacogenetics, organ impairment, age, race, sex, weight, and so on.

The function of the drug product label

The drug label/SmPC/product-information leaflet (PIL) is the source of information for healthcare professionals and patients on how to use the medicine effectively and safely. The drug label can be likened to a “contract” between the Market Application Holder and the Regulatory Agency. All claims and recommendations in the label/SmPC/PIL need to be supported with data and a large part of this information is based on clinical pharmacology studies (see below).

Clinical pharmacology information in the package insert

Product Labeling

• PK/PD, Effectiveness/Safety, and Dose/Dose Adjustment
  • QTc (drug effect on corrected QT interval)
    PK/Bioavailability
    Food Effect
    Metabolism/Transport (DDI, Mass Balance)
    Pediatrics/Elderly
    Hepatic Impairment
    Renal Impairment
    Pharmacogenomics
    Immunogenicity (Biologics)[i]

Taking it from the beginning: The first clinical studies

The first clinical studies are conducted on healthy subjects in what are known as single ascending dose (SAD) and multiple ascending dose (MAD) studies. In these studies, safety and tolerability are examined, and pharmacokinetics is also a key objective.

As the drug development program advances to include the intended patient population, understanding the potential for drug-drug interactions (DDI) becomes valuable, as a patient typically needs to take other drugs during the clinical study. The potential for DDIs is initially studied through in vitro experiments using human biomaterials like liver microsomes, hepatocytes, and cells transfected with transporter protein. These assays give information on how the investigational drug is affected by or affects drug-metabolizing enzymes and drug transporters known to be important for drug interactions. Based on these in vitro data, the risk of clinically relevant DDIs can be assessed. If a DDI risk cannot be excluded, such as when the investigational drug is a strong CYP3A4 inhibitor in vitro, sensitive CYP3A4 substrates should be prohibited in clinical studies until the effect has been evaluated in humans. After performing a dedicated DDI study in humans, recommendations in the label can be made on how to use the combination safely or if a specific combination should be contraindicated.

To see the full picture

The multitude of clinical pharmacology studies are necessary to adequately assess a new medical product (see Figure 1). These studies are costly and can be overwhelming and it is therefore important for a sponsor to determine its acceptable risk level and to carefully plan the clinical pharmacology program. For instance, the required, but expensive, human mass balance study can be postponed. However, the choice to do so must be balanced against the risk of delaying the discovery of critical drug attributes that need to be further evaluated in clinical studies. This could delay the timeline for submitting a Marketing Authorization Application (MAA) to the EMA or New Drug Application (NDA) to the U.S. FDA.

Figure 1: Timing of early nonclinical drug metabolism and PK (DMPK) studies and clinical pharmacology studies

ADME, Absorption, distribution, metabolism and excretion; CYP, cytochrome P; DDI, drug-drug interaction; FIH, First-in-human; MAD, multiple ascending dose; NOAEL, No-observed-adverse-effect-level; PBPK, Physiologically based pharmacokinetics; SAD, Single ascending dose; TQT, thorough QT

Strategic guidance for conducting clinical pharmacology studies

Preclinical requirements and study design for Phase I readiness

When preparing for clinical development, companies often seek expertise primarily on the preclinical package before entering Phase I. A common query we address is whether any essential studies are lacking before a first-in-human trial — what information do regulators require at this stage of development? Cytel experts within clinical pharmacology are experienced in performing a preclinical gap analysis and determining a safe starting dose based on available nonclinical data. Our expertise also encompasses the design of clinical studies to generate data necessary for optimal clinical development.

Dosing strategy based on pharmacokinetics and pharmacodynamics

Sponsors often require expertise in establishing optimal dosing strategies for clinical trials. This process requires a comprehensive analysis of pharmacokinetic and pharmacodynamic data. Simple allometric scaling can sometimes be used to predict human dose based on animal PK data. But a more rational way includes combing more data using simulation and modeling, which is encouraged by regulatory bodies. Within Cytel, we use PKPD and PBPK modeling. PKPD modelling is effective at establishing a relationship between dose and relevant PK and PD endpoints, while physiologically based pharmacokinetic (PBPK) models are superior for mechanistic evaluations.

Mitigating risks across patient populations

A comprehensive understanding of a drug allows us to mitigate the risks of suboptimal dosing across diverse patient populations. For instance, drugs with high renal excretion necessitate careful consideration of renal function when determining dose levels and regimens. Often a renal impairment study is warranted for these drugs. This is because an impaired renal function can increase the drug’s half-life and thus risk of accumulation during repeat dosing. This scenario often mandates dose reduction, extended dosing intervals, or both, in patients with renal impairments.

Serving as an expert while communicating with authority

Within Cytel, one of our most common tasks is to help prepare regulatory scientific documents and to serve as experts when communicating with competent authority. It is usually recommended to meet with competent authority for scientific advice at least once during development. In early phases of drug development, typical questions include:

• Do you agree that the preclinical package is sufficient at this stage of development?
• Do you agree with the suggestion for starting dose?
• Do you agree with the clinical design suggested for the first-in-human trial?

It is critical to get the authority view on a planned study at an early stage and that questions are properly formulated. This is to identify and resolve outstanding issues before starting a trial or initiating a study. Doing this will avoid problems and save resources later in development.

Final takeaways

Clinical pharmacology studies are critical for mitigating risk for patients. To conduct these as efficiently and effectively as possible, sponsors should involve experts early on in drug development, which will also help ensure appropriate timing and budget.

Cytel’s experts within clinical pharmacology and DMPK can help sponsors during the entire drug development process, including early preclinical studies, clinical studies, building submission packages for competent authorities, and suggesting the label wording.

Notes

[i] Liu, Q., Ahadpour, M., Rocca, M., & Huang, S.-M. (2021). Clinical Pharmacology Regulatory Sciences in Drug Development and Precision Medicine: Current Status and Emerging Trends. The AAPS Journal, 23(54). https://doi.org/10.1208/s12248-021-00563-3

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